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Frontiers of Medicine

, Volume 9, Issue 1, pp 10–19 | Cite as

Th17 cells in autoimmune diseases

  • Lei Han
  • Jing Yang
  • Xiuwen Wang
  • Dan Li
  • Ling Lv
  • Bin Li
Review

Abstract

Th17 cells are a new subset of CD4+ T cells involved in the clearance of extracellular pathogens and fungi. Accumulating evidence suggests that Th17 cells and their signature cytokines have a pivotal role in the pathogenesis of multiple autoimmune-mediated inflammatory diseases. Here, we summarize recent research progress on Th17 function in the development and pathogenesis of autoimmune diseases. We also propose to identify new small molecule compounds to manipulate Th17 function for potential therapeutic application to treat human autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, inflammatory bowel disease, and multiple sclerosis.

Keywords

IL-17 Th17 cells RORγt autoimmune diseases posttranslational modification inhibitors 

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References

  1. 1.
    Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003; 421(6924): 744–748PubMedGoogle Scholar
  2. 2.
    Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003; 198(12): 1951–1957PubMedCentralPubMedGoogle Scholar
  3. 3.
    Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6(11): 1133–1141PubMedCentralPubMedGoogle Scholar
  4. 4.
    Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 2008; 28(4): 454–467PubMedCentralPubMedGoogle Scholar
  5. 5.
    Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT. Transforming growth factor-beta induces development of the T(H) 17 lineage. Nature 2006; 441(7090): 231–234PubMedGoogle Scholar
  6. 6.
    Bedoya SK, Lam B, Lau K, Larkin J 3rd. Th17 cells in immunity and autoimmunity. Clin Dev Immunol 2013; 2013: 986789PubMedCentralPubMedGoogle Scholar
  7. 7.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441(7090): 235–238PubMedGoogle Scholar
  8. 8.
    Wei L, Laurence A, Elias KM, O’Shea JJ. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem 2007; 282(48): 34605–34610PubMedCentralPubMedGoogle Scholar
  9. 9.
    Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of T(H)17 cells. Nature 2008; 453(7198): 1051–1057PubMedGoogle Scholar
  10. 10.
    Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 2007; 8(9): 942–949PubMedGoogle Scholar
  11. 11.
    Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupé P, Barillot E, Soumelis V. A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol 2008; 9(6): 650–657PubMedGoogle Scholar
  12. 12.
    Manel N, Unutmaz D, Littman DR. The differentiation of human T (H)-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORgt. Nat Immunol 2008; 9(6): 641–649PubMedCentralPubMedGoogle Scholar
  13. 13.
    Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006; 126(6): 1121–1133PubMedGoogle Scholar
  14. 14.
    Ichiyama K, Yoshida H, Wakabayashi Y, Chinen T, Saeki K, Nakaya M, Takaesu G, Hori S, Yoshimura A, Kobayashi T. Foxp3 inhibits RORgt-mediated IL-17A mRNA transcription through direct interaction with RORgt. J Biol Chem 2008; 283(25): 17003–17008PubMedGoogle Scholar
  15. 15.
    Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORg. Immunity 2008; 28(1): 29–39PubMedCentralPubMedGoogle Scholar
  16. 16.
    Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 2007; 282(13): 9358–9363PubMedGoogle Scholar
  17. 17.
    Brüstle A, Heink S, Huber M, Rosenplänter C, Stadelmann C, Yu P, Arpaia E, Mak TW, Kamradt T, Lohoff M. The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol 2007; 8(9): 958–966PubMedGoogle Scholar
  18. 18.
    Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M, Weiner HL. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 2008; 453(7191): 65–71PubMedGoogle Scholar
  19. 19.
    Liu C, Qian W, Qian Y, Giltiay NV, Lu Y, Swaidani S, Misra S, Deng L, Chen ZJ, Li X. Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. Sci Signal 2009; 2(92): ra63PubMedCentralPubMedGoogle Scholar
  20. 20.
    Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, Wu C, Kleinewietfeld M, Kunder S, Hafler DA, Sobel RA, Regev A, Kuchroo VK. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 2012; 13(10): 991–999PubMedCentralPubMedGoogle Scholar
  21. 21.
    Benedetti G, Miossec P. Interleukin 17 contributes to the chronicity of inflammatory diseases such as rheumatoid arthritis. Eur J Immunol 2014; 44(2): 339–347PubMedGoogle Scholar
  22. 22.
    Metawi SA, Abbas D, Kamal MM, Ibrahim MK. Serum and synovial fluid levels of interleukin-17 in correlation with disease activity in patients with RA. Clin Rheumatol 2011; 30(9): 1201–1207PubMedGoogle Scholar
  23. 23.
    Suurmond J, Dorjée AL, Boon MR, Knol EF, Huizinga TW, Toes RE, Schuerwegh AJ. Mast cells are the main interleukin 17-positive cells in anticitrullinated protein antibody-positive andnegative rheumatoid arthritis and osteoarthritis synovium. Arthritis Res Ther 2011; 13(5): R150PubMedCentralPubMedGoogle Scholar
  24. 24.
    Park JS, Park MK, Lee SY, Oh HJ, Lim MA, Cho WT, Kim EK, Ju JH, Park YW, Park SH, Cho ML, Kim HY. TWEAK promotes the production of interleukin-17 in rheumatoid arthritis. Cytokine 2012; 60(1): 143–149PubMedGoogle Scholar
  25. 25.
    Lubberts E, Koenders MI, van den Berg WB. The role of T-cell interleukin-17 in conducting destructive arthritis: lessons from animal models. Arthritis Res Ther 2005; 7(1): 29–37PubMedCentralPubMedGoogle Scholar
  26. 26.
    Chao CC, Chen SJ, Adamopoulos IE, Davis N, Hong K, Vu A, Kwan S, Fayadat-Dilman L, Asio A, Bowman EP. Anti-IL-17A therapy protects against bone erosion in experimental models of rheumatoid arthritis. Autoimmunity 2011; 44(3): 243–252PubMedGoogle Scholar
  27. 27.
    Kellner H. Targeting interleukin-17 in patients with active rheumatoid arthritis: rationale and clinical potential. Ther Adv Musculoskelet Dis; 5(3): 141–152Google Scholar
  28. 28.
    Patel DD, Lee DM, Kolbinger F, Antoni C. Effect of IL-17A blockade with secukinumab in autoimmune diseases. Ann Rheum Dis 2013; 72(Suppl 2): ii116–ii123PubMedGoogle Scholar
  29. 29.
    Jain M, Attur M, Furer V, Todd J, Ramirez R, Lock M, Lu QA, Abramson SB, Greenberg JD. Increased plasma IL-17F levels in rheumatoid arthritis patients are responsive to methotrexate, anti-TNF, and T Cell costimulatory modulation. Inflammation 2014 Sep 21. [Epub ahead of print]Google Scholar
  30. 30.
    Hirota K, Hashimoto M, Yoshitomi H, Tanaka S, Nomura T, Yamaguchi T, Iwakura Y, Sakaguchi N, Sakaguchi S. T cell selfreactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis. J Exp Med 2007; 204(1): 41–47PubMedCentralPubMedGoogle Scholar
  31. 31.
    Leipe J, Schramm MA, Prots I, Schulze-Koops H, Skapenko A. Increased Th17 cell frequency and poor clinical outcome in rheumatoid arthritis are associated with a genetic variant in the IL4R gene, rs1805010. Arthritis Rheum (Munch) 2014; 66(5): 1165–1175Google Scholar
  32. 32.
    Shen H, Goodall JC, Hill Gaston JS. Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum 2009; 60(6): 1647–1656PubMedGoogle Scholar
  33. 33.
    van Hamburg JP, Asmawidjaja PS, Davelaar N, Mus AM, Colin EM, Hazes JM, Dolhain RJ, Lubberts E. Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. Arthritis Rheum 2011; 63(1): 73–83PubMedGoogle Scholar
  34. 34.
    Zhang L, Li YG, Li YH, Qi L, Liu XG, Yuan CZ, Hu NW, Ma DX, Li ZF, Yang Q, Li W, Li JM. Increased frequencies of Th22 cells as well as Th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis. PLoS ONE 2012; 7(4): e31000PubMedCentralPubMedGoogle Scholar
  35. 35.
    van Hamburg JP, Corneth OB, Paulissen SM, Davelaar N, Asmawidjaja PS, Mus AM, Lubberts E. IL-17/Th17 mediated synovial inflammation is IL-22 independent. Ann Rheum Dis 2013; 72(10): 1700–1707PubMedGoogle Scholar
  36. 36.
    Kim J, Kang S, Kim J, Kwon G, Koo S. Elevated levels of T helper 17 cells are associated with disease activity in patients with rheumatoid arthritis. Ann Lab Med 2013; 33(1): 52–59PubMedCentralPubMedGoogle Scholar
  37. 37.
    Church LD, Filer AD, Hidalgo E, Howlett KA, Thomas AM, Rapecki S, Scheel-Toellner D, Buckley CD, Raza K. Rheumatoid synovial fluid interleukin-17-producing CD4 T cells have abundant tumor necrosis factor-α co-expression, but little interleukin-22 and interleukin-23R expression. Arthritis Res Ther 2010; 12(5): R184PubMedCentralPubMedGoogle Scholar
  38. 38.
    Nistala K, Adams S, Cambrook H, Ursu S, Olivito B, de Jager W, Evans JG, Cimaz R, Bajaj-Elliott M, Wedderburn LR. Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci USA 2010; 107(33): 14751–14756PubMedCentralPubMedGoogle Scholar
  39. 39.
    Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, Tanaka S, Kodama T, Akira S, Iwakura Y, Cua DJ, Takayanagi H. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 2006; 203(12): 2673–2682PubMedCentralPubMedGoogle Scholar
  40. 40.
    Hickman-Brecks CL, Racz JL, Meyer DM, LaBranche TP, Allen PM. Th17 cells can provide B cell help in autoantibody induced arthritis. J Autoimmun 2011; 36(1): 65–75PubMedCentralPubMedGoogle Scholar
  41. 41.
    Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, Tanaka S, Bluestone JA, Takayanagi H. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med 2014; 20(1): 62–68PubMedGoogle Scholar
  42. 42.
    Shlomchik MJ, Craft JE, Mamula MJ. From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol 2001; 1(2): 147–153PubMedGoogle Scholar
  43. 43.
    Wong CK, Lit LC, Tam LS, Li EK, Wong PT, Lam CW. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol 2008; 127(3): 385–393PubMedGoogle Scholar
  44. 44.
    Zhao XF, Pan HF, Yuan H, Zhang WH, Li XP, Wang GH, Wu GC, Su H, Pan FM, Li WX, Li LH, Chen GP, Ye DQ. Increased serum interleukin 17 in patients with systemic lupus erythematosus. Mol Biol Rep 2010; 37(1): 81–85PubMedGoogle Scholar
  45. 45.
    Cheng F, Guo Z, Xu H, Yan D, Li Q. Decreased plasma IL22 levels, but not increased IL17 and IL23 levels, correlate with disease activity in patients with systemic lupus erythematosus. Ann Rheum Dis 2009; 68(4): 604–606PubMedGoogle Scholar
  46. 46.
    Vincent FB, Northcott M, Hoi A, Mackay F, Morand EF. Clinical associations of serum interleukin-17 in systemic lupus erythematosus. Arthritis Res Ther 2013; 15(4): R97PubMedCentralPubMedGoogle Scholar
  47. 47.
    Amarilyo G, Lourenço EV, Shi FD, La Cava A. IL-17 promotes murine lupus. J Immunol 2014; 193(2): 540–543PubMedGoogle Scholar
  48. 48.
    Xing Q, Wang B, Su H, Cui J, Li J. Elevated Th17 cells are accompanied by FoxP3+ Treg cells decrease in patients with lupus nephritis. Rheumatol Int 2012; 32(4): 949–958PubMedGoogle Scholar
  49. 49.
    Kato H, Perl A. Mechanistic target of rapamycin complex 1 expands Th17 and IL-4+ CD4-CD8-double-negative T cells and contracts regulatory T cells in systemic lupus erythematosus. J Immunol 2014; 192(9): 4134–4144PubMedGoogle Scholar
  50. 50.
    Crispín JC, Oukka M, Bayliss G, Cohen RA, Van Beek CA, Stillman IE, Kyttaris VC, Juang YT, Tsokos GC. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol 2008; 181(12): 8761–8766PubMedCentralPubMedGoogle Scholar
  51. 51.
    Mizui M, Koga T, Lieberman LA, Beltran J, Yoshida N, Johnson MC, Tisch R, Tsokos GC. IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4-CD8-IL-17-producing T cells. J Immunol 2014; 193(5): 2168–2177PubMedGoogle Scholar
  52. 52.
    Shah K, Lee WW, Lee SH, Kim SH, Kang SW, Craft J, Kang I. Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus. Arthritis Res Ther 2010; 12(2): R53PubMedCentralPubMedGoogle Scholar
  53. 53.
    Yang XY, Wang HY, Zhao XY, Wang LJ, Lv QH, Wang QQ. Th22, but not Th17 might be a good index to predict the tissue involvement of systemic lupus erythematosus. J Clin Immunol 2013; 33(4): 767–774PubMedGoogle Scholar
  54. 54.
    Yang J, Chu Y, Yang X, Gao D, Zhu L, Yang X, Wan L, Li M. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum 2009; 60(5): 1472–1483PubMedGoogle Scholar
  55. 55.
    Chen DY, Chen YM, Wen MC, Hsieh TY, Hung WT, Lan JL. The potential role of Th17 cells and Th17-related cytokines in the pathogenesis of lupus nephritis. Lupus 2012; 21(13): 1385–1396PubMedGoogle Scholar
  56. 56.
    Dolff S, Bijl M, Huitema MG, Limburg PC, Kallenberg CG, Abdulahad WH. Disturbed Th1, Th2, Th17 and T(reg) balance in patients with systemic lupus erythematosus. Clin Immunol 2011; 141(2): 197–204PubMedGoogle Scholar
  57. 57.
    Voulgarelis M, Tzioufas AG. Pathogenetic mechanisms in the initiation and perpetuation of Sjögren’s syndrome. Nat Rev Rheumatol 2010; 6(9): 529–537PubMedGoogle Scholar
  58. 58.
    Jonsson R, Vogelsang P, Volchenkov R, Espinosa A, Wahren-Herlenius M, Appel S. The complexity of Sjögren’s syndrome: novel aspects on pathogenesis. Immunol Lett 2011; 141(1): 1–9PubMedGoogle Scholar
  59. 59.
    Singh N, Cohen PL. The T cell in Sjogren’s syndrome: force majeure, not spectateur. J Autoimmun 2012; 39(3): 229–233PubMedCentralPubMedGoogle Scholar
  60. 60.
    Fox RI, Adamson TC 3rd, Fong S, Young C, Howell FV. Characterization of the phenotype and function of lymphocytes infiltrating the salivary gland in patients with primary Sjögren syndrome. Diagn Immunol 1983; 1(3): 233–239PubMedGoogle Scholar
  61. 61.
    Lin X, Tian J, Rui K, Ma KY, Ko KH, Wang S, Lu L. The role of T helper 17 cell subsets in Sjögren’s syndrome: similarities and differences between mouse model and humans. Ann Rheum Dis 2014; 73(7): e43PubMedGoogle Scholar
  62. 62.
    Nguyen CQ, Yin H, Lee BH, Carcamo WC, Chiorini JA, Peck AB. Pathogenic effect of interleukin-17A in induction of Sjögren’s syndrome-like disease using adenovirus-mediated gene transfer. Arthritis Res Ther 2010; 12(6): R220PubMedCentralPubMedGoogle Scholar
  63. 63.
    Ciccia F, Guggino G, Rizzo A, Ferrante A, Raimondo S, Giardina A, Dieli F, Campisi G, Alessandro R, Triolo G. Potential involvement of IL-22 and IL-22-producing cells in the inflamed salivary glands of patients with Sjögren’s syndrome. Ann Rheum Dis 2012; 71(2): 295–301PubMedGoogle Scholar
  64. 64.
    Nguyen CQ, Hu MH, Li Y, Stewart C, Peck AB. Salivary gland tissue expression of interleukin-23 and interleukin-17 in Sjögren’s syndrome: findings in humans and mice. Arthritis Rheum 2008; 58(3): 734–743PubMedCentralPubMedGoogle Scholar
  65. 65.
    Sakai A, Sugawara Y, Kuroishi T, Sasano T, Sugawara S. Identification of IL-18 and Th17 cells in salivary glands of patients with Sjögren’s syndrome, and amplification of IL-17-mediated secretion of inflammatory cytokines from salivary gland cells by IL-18. J Immunol 2008; 181(4): 2898–2906PubMedGoogle Scholar
  66. 66.
    Katsifis GE, Rekka S, Moutsopoulos NM, Pillemer S, Wahl SM. Systemic and local interleukin-17 and linked cytokines associated with Sjögren’s syndrome immunopathogenesis. Am J Pathol 2009; 175(3): 1167–1177PubMedCentralPubMedGoogle Scholar
  67. 67.
    Fei Y, Zhang W, Lin D, Wu C, Li M, Zhao Y, Zeng X, Zhang F. Clinical parameter and Th17 related to lymphocytes infiltrating degree of labial salivary gland in primary Sjögren’s syndrome. Clin Rheumatol 2014; 33(4): 523–529PubMedGoogle Scholar
  68. 68.
    Youinou P, Pers JO. Disturbance of cytokine networks in Sjögren’s syndrome. Arthritis Res Ther 2011; 13(4): 227PubMedCentralPubMedGoogle Scholar
  69. 69.
    Alunno A, Bistoni O, Bartoloni E, Caterbi S, Bigerna B, Tabarrini A, Mannucci R, Falini B, Gerli R. IL-17-producing CD4-CD8-T cells are expanded in the peripheral blood, infiltrate salivary glands and are resistant to corticosteroids in patients with primary Sjögren’s syndrome. Ann Rheum Dis 2013; 72(2): 286–292PubMedGoogle Scholar
  70. 70.
    Alunno A, Carubbi F, Bistoni O, Caterbi S, Bartoloni E, Bigerna B, Pacini R, Beghelli D, Cipriani P, Giacomelli R, Gerli R. CD4(-) CD8(-) T-cells in primary Sjögren’s syndrome: association with the extent of glandular involvement. J Autoimmun 2014; 51: 38–43PubMedGoogle Scholar
  71. 71.
    Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol 2010; 28(1): 573–621PubMedGoogle Scholar
  72. 72.
    Di Sabatino A, Biancheri P, Rovedatti L, MacDonald TT, Corazza GR. New pathogenic paradigms in inflammatory bowel disease. Inflamm Bowel Dis 2012; 18(2): 368–371PubMedGoogle Scholar
  73. 73.
    Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002; 347(6): 417–429PubMedGoogle Scholar
  74. 74.
    Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, Bamba T, Fujiyama Y. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 2003; 52(1): 65–70PubMedCentralPubMedGoogle Scholar
  75. 75.
    Seiderer J, Elben I, Diegelmann J, Glas J, Stallhofer J, Tillack C, Pfennig S, Jürgens M, Schmechel S, Konrad A, Göke B, Ochsenkühn T, Müller-Myhsok B, Lohse P, Brand S. Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn’s disease and analysis of the IL17F p. His161Arg polymorphism in IBD. Inflamm Bowel Dis 2008; 14(4): 437–445PubMedGoogle Scholar
  76. 76.
    Zenewicz LA, Antov A, Flavell RA. CD4 T-cell differentiation and inflammatory bowel disease. Trends Mol Med 2009; 15(5): 199–207PubMedGoogle Scholar
  77. 77.
    Feng T, Qin H, Wang L, Benveniste EN, Elson CO, Cong Y. Th17 cells induce colitis and promote Th1 cell responses through IL-17 induction of innate IL-12 and IL-23 production. J Immunol 2011; 186(11): 6313–6318PubMedCentralPubMedGoogle Scholar
  78. 78.
    Lees CW, Barrett JC, Parkes M, Satsangi J. New IBD genetics: common pathways with other diseases. Gut 2011; 60(12): 1739–1753PubMedGoogle Scholar
  79. 79.
    Caprioli F, Bosè F, Rossi RL, Petti L, Viganò C, Ciafardini C, Raeli L, Basilisco G, Ferrero S, Pagani M, Conte D, Altomare G, Monteleone G, Abrignani S, Reali E. Reduction of CD68+ macrophages and decreased IL-17 expression in intestinal mucosa of patients with inflammatory bowel disease strongly correlate with endoscopic response and mucosal healing following infliximab therapy. Inflamm Bowel Dis 2013; 19(4): 729–739PubMedGoogle Scholar
  80. 80.
    Geremia A, Biancheri P, Allan P, Corazza GR, Di Sabatino A. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev 2014; 13(1): 3–10PubMedGoogle Scholar
  81. 81.
    Yang XO, Chang SH, Park H, Nurieva R, Shah B, Acero L, Wang YH, Schluns KS, Broaddus RR, Zhu Z, Dong C. Regulation of inflammatory responses by IL-17F. J Exp Med 2008; 205(5): 1063–1075PubMedCentralPubMedGoogle Scholar
  82. 82.
    O’Connor W Jr, Kamanaka M, Booth CJ, Town T, Nakae S, Iwakura Y, Kolls JK, Flavell RA. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol 2009; 10(6): 603–609PubMedCentralPubMedGoogle Scholar
  83. 83.
    Zhang Z, Zheng M, Bindas J, Schwarzenberger P, Kolls JK. Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis 2006; 12(5): 382–388PubMedGoogle Scholar
  84. 84.
    Troncone E, Marafini I, Pallone F, Monteleone G. Th17 cytokines in inflammatory bowel diseases: discerning the good from the bad. Int Rev Immunol 2013; 32(5–6): 526–533PubMedGoogle Scholar
  85. 85.
    Sarra M, Pallone F, Macdonald TT, Monteleone G. IL-23/IL-17 axis in IBD. Inflamm Bowel Dis 2010; 16(10): 1808–1813PubMedGoogle Scholar
  86. 86.
    Morrison PJ, Bending D, Fouser LA, Wright JF, Stockinger B, Cooke A, Kullberg MC. Th17-cell plasticity in Helicobacter hepaticus-induced intestinal inflammation. Mucosal Immunol 2013; 6(6): 1143–1156PubMedGoogle Scholar
  87. 87.
    Morrison PJ, Ballantyne SJ, Kullberg MC. Interleukin-23 and T helper 17-type responses in intestinal inflammation: from cytokines to T-cell plasticity. Immunology 2011; 133(4): 397–408PubMedCentralPubMedGoogle Scholar
  88. 88.
    Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD, Wehkamp J, Feagan BG, Yao MD, Karczewski M, Karczewski J, Pezous N, Bek S, Bruin G, Mellgard B, Berger C, Londei M, Bertolino AP, Tougas G, Travis SP; Secukinumab in Crohn’s Disease Study Group. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 2012; 61(12): 1693–1700PubMedGoogle Scholar
  89. 89.
    McFarland HF, Martin R. Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 2007; 8(9): 913–919PubMedGoogle Scholar
  90. 90.
    Voskuhl RR, Martin R, Bergman C, Dalal M, Ruddle NH, McFarland HF. T helper 1 (Th1) functional phenotype of human myelin basic protein-specific T lymphocytes. Autoimmunity 1993; 15(2): 137–143PubMedGoogle Scholar
  91. 91.
    Kroenke MA, Chensue SW, Segal BM. EAE mediated by a non-IFN-γ/non-IL-17 pathway. Eur J Immunol 2010; 40(8): 2340–2348PubMedCentralPubMedGoogle Scholar
  92. 92.
    Jäger A, Dardalhon V, Sobel RA, Bettelli E, Kuchroo VK. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol 2009; 183(11): 7169–7177PubMedCentralPubMedGoogle Scholar
  93. 93.
    Romme Christensen J, Börnsen L, Ratzer R, Piehl F, Khademi M, Olsson T, Sørensen PS, Sellebjerg F. Systemic inflammation in progressive multiple sclerosis involves follicular T-helper, Th17- and activated B-cells and correlates with progression. PLoS ONE 2013; 8(3): e57820PubMedGoogle Scholar
  94. 94.
    Tao Y, Zhang X, Chopra M, Kim MJ, Buch KR, Kong D, Jin J, Tang Y, Zhu H, Jewells V, Markovic-Plese S. The role of endogenous IFN-β in the regulation of Th17 responses in patients with relapsing-remitting multiple sclerosis. J Immunol 2014; 192(12): 5610–5617PubMedGoogle Scholar
  95. 95.
    Coquet JM, Middendorp S, van der Horst G, Kind J, Veraar EA, Xiao Y, Jacobs H, Borst J. The CD27 and CD70 costimulatory pathway inhibits effector function of T helper 17 cells and attenuates associated autoimmunity. Immunity 2013; 38(1): 53–65PubMedGoogle Scholar
  96. 96.
    Haak S, Croxford AL, Kreymborg K, Heppner FL, Pouly S, Becher B, Waisman A. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J Clin Invest 2009; 119(1): 61–69PubMedCentralPubMedGoogle Scholar
  97. 97.
    Kreymborg K, Etzensperger R, Dumoutier L, Haak S, Rebollo A, Buch T, Heppner FL, Renauld JC, Becher B. IL-22 is expressed by Th17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis. J Immunol 2007; 179(12): 8098–8104PubMedGoogle Scholar
  98. 98.
    Sonderegger I, Kisielow J, Meier R, King C, Kopf M. IL-21 and IL-21R are not required for development of Th17 cells and autoimmunity in vivo. Eur J Immunol 2008; 38(7): 1833–1838PubMedGoogle Scholar
  99. 99.
    Codarri L, Gyülvészi G, Tosevski V, Hesske L, Fontana A, Magnenat L, Suter T, Becher B. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 2011; 12(6): 560–567PubMedGoogle Scholar
  100. 100.
    El-Behi M, Ciric B, Dai H, Yan Y, Cullimore M, Safavi F, Zhang GX, Dittel BN, Rostami A. The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol 2011; 12(6): 568–575PubMedCentralPubMedGoogle Scholar
  101. 101.
    Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Muller DN, Hafler DA. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 2013; 496(7446): 518–522PubMedCentralPubMedGoogle Scholar
  102. 102.
    Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, Lira S, Uccelli A, Lanzavecchia A, Engelhardt B, Sallusto F. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 2009; 10(5): 514–523PubMedGoogle Scholar
  103. 103.
    Maddur MS, Miossec P, Kaveri SV, Bayry J. Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. Am J Pathol 2012; 181(1): 8–18PubMedGoogle Scholar
  104. 104.
    Krueger GG, Langley RG, Leonardi C, Yeilding N, Guzzo C, Wang Y, Dooley LT, Lebwohl M; CNTO 1275 Psoriasis Study Group. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 2007; 356(6): 580–592PubMedGoogle Scholar
  105. 105.
    Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, Katz S, Johanns J, Blank M, Rutgeerts P; Ustekinumab Crohn’s Disease Study Group. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology 2008; 135(4): 1130–1141PubMedGoogle Scholar
  106. 106.
    Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, Antoni C, Draelos Z, Gold MH; Psoriasis Study Group, Durez P, Tak PP, Gomez-Reino JJ; Rheumatoid Arthritis Study Group, Foster CS, Kim RY, Samson CM, Falk NS, Chu DS, Callanan D, Nguyen QD; Uveitis Study Group, Rose K, Haider A, Di Padova F. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med 2010; 2(52): 52ra72PubMedGoogle Scholar
  107. 107.
    Genovese MC, Van den Bosch F, Roberson SA, Bojin S, Biagini IM, Ryan P, Sloan-Lancaster J. LY2439821, a humanized antiinterleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study. Arthritis Rheum 2010; 62(4): 929–939PubMedGoogle Scholar
  108. 108.
    Huh JR, Littman DR. Small molecule inhibitors of RORγt: targeting Th17 cells and other applications. Eur J Immunol 2012; 42(9): 2232–2237PubMedCentralPubMedGoogle Scholar
  109. 109.
    Huh JR, Leung MW, Huang P, Ryan DA, Krout MR, Malapaka RR, Chow J, Manel N, Ciofani M, Kim SV, Cuesta A, Santori FR, Lafaille JJ, Xu HE, Gin DY, Rastinejad F, Littman DR. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity. Nature 2011; 472(7344): 486–490PubMedCentralPubMedGoogle Scholar
  110. 110.
    Solt LA, Kumar N, Nuhant P, Wang Y, Lauer JL, Liu J, Istrate MA, Kamenecka TM, Roush WR, Vidović D, Schürer SC, Xu J, Wagoner G, Drew PD, Griffin PR, Burris TP. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 2011; 472(7344): 491–494PubMedCentralPubMedGoogle Scholar
  111. 111.
    Xu T, Wang X, Zhong B, Nurieva RI, Ding S, Dong C. Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORgt protein. J Biol Chem 2011; 286(26): 22707–22710PubMedCentralPubMedGoogle Scholar
  112. 112.
    Cascão R, Vidal B, Raquel H, Neves-Costa A, Figueiredo N, Gupta V, Fonseca JE, Moita LF. Effective treatment of rat adjuvantinduced arthritis by celastrol. Autoimmun Rev 2012; 11(12): 856–862PubMedCentralPubMedGoogle Scholar
  113. 113.
    Xiao S, Yosef N, Yang J, Wang Y, Zhou L, Zhu C, Wu C, Baloglu E, Schmidt D, Ramesh R, Lobera M, Sundrud MS, Tsai PY, Xiang Z, Wang J, Xu Y, Lin X, Kretschmer K, Rahl PB, Young RA, Zhong Z, Hafler DA, Regev A, Ghosh S, Marson A, Kuchroo VK. Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity 2014; 40(4): 477–489PubMedGoogle Scholar
  114. 114.
    Xie L, Chen J, McMickle A, Awar N, Nady S, Sredni B, Drew PD, Yu S. The immunomodulator AS101 suppresses production of inflammatory cytokines and ameliorates the pathogenesis of experimental autoimmune encephalomyelitis. J Neuroimmunol 2014; 273(1–2): 31–41PubMedGoogle Scholar
  115. 115.
    Zhong B, Liu X, Wang X, Chang SH, Liu X, Wang A, Reynolds JM, Dong C. Negative regulation of IL-17-mediated signaling and inflammation by the ubiquitin-specific protease USP25. Nat Immunol 2012; 13(11): 1110–1117PubMedCentralPubMedGoogle Scholar
  116. 116.
    Han L, Yang J, Wang X, Wu Q, Yin S, Li Z, Zhang J, Xing Y, Chen Z, Tsun A, Li D, Piccioni M, Zhang Y, Guo Q, Jiang L, Bao L, Lv L, Li B. The E3 deubiquitinase USP17 is a positive regulator of retinoic acid-related orphan nuclear receptor γt (RORγt) in Th17 cells. J Biol Chem 2014; 289(37): 25546–25555PubMedGoogle Scholar
  117. 117.
    Pal A, Young MA, Donato NJ. Emerging potential of therapeutic targeting of ubiquitin-specific proteases in the treatment of cancer. Cancer Res 2014; 74(18): 4955–4966PubMedGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Division of Rheumatology, Huashan HospitalFudan UniversityShanghaiChina
  2. 2.Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological SciencesChinese Academy of SciencesShanghaiChina

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